BACKGROUND: Gastric cancer and esophageal cancer are the second and sixth most common causes of cancer death worldwide. Both of these upper gastrointestinal tract (UGI) cancers have a very poor prognosis, largely because symptoms usually do not occur until late in the disease. Significant reduction in UGI cancer mortality will probably require development of new prevention strategies based on identification of new modifiable risk factors and development of new methods to diagnose and treat more cases at earlier, more curable stages of disease. PURPOSE: The aims of this project are (1) to examine hypotheses relating to the etiology and prevention of upper gastrointestinal cancers, and (2) to develop successful clinical strategies for the early detection and treatment of these cancers. METHODS: Both etiologic and early detection studies are most efficiently done in high-risk populations, so many of the studies in this project are performed in such populations. (1) Etiologic studies: (a) China: Between 1985 and 1991, we conducted two randomized nutrition intervention trials (NIT), in Linxian, China, a county where cumulative death rates due to esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) exceed 20%. These trials, with a combined enrollment of nearly 33,000 people, evaluated the effect of supplementation with several vitamin/mineral combinations on UGI cancers and found significant reductions in total mortality and gastric cancer mortality among those taking a combination of selenium, beta-carotene and vitamin E. Since 1991, we have followed the NIT participants as a cohort, and have performed nested studies evaluating the association between baseline characteristics and later development of UGI cancers. In addition, we have performed other etiologic studies specifically designed to evaluate individual exposures such as polycyclic aromatic hydrocarbons (PAHs), acetaldehyde, human papillomavirus (HPV), and Helicobacter pylori (H. pylori). (b) Iran: We have recently performed two etiologic studies in Golestan Province, Iran, another population with very high rates of ESCC. Between 2003 and 2007, the Golestan Case-Control Study enrolled 300 ESCC cases, 571 neighborhood controls and 300 clinic controls, and between 2004 and 2008 the Golestan Cohort Study enrolled 50,000 participants. Comparing results from high-risk populations in Iran and China, which are quite distinct geographically, ethnically and culturally, should give us insight into which environmental and genetic risk factors are most important for the development of this disease. (c) Brazil: We have performed several studies evaluating PAH exposure in a high ESCC risk population in southern Brazil; (d) Kenya: We have completed a feasibility study for a case-control study of ESCC in western Kenya, which has high rates of this disease and the unusual occurrence of 8% of the cases in individuals younger than 30 years old. (2) Early Detection of Esophageal Cancer: This part of the project includes three studies: (a) the Primary Screening Studies, to develop practical and accurate primary screening tests for esophageal squamous dysplasia and early ESCC; (b) Endoscopic Evaluation Studies, to develop methods for endoscopic localization and evaluation of esophageal squamous dysplasia; and (c) Endoscopic Therapy Studies, to evaluate new techniques for endoscopic treatment of high-grade squamous dysplasia and early ESCC. PROGRESS: (1) Etiologic studies: (a) China: Recent follow-up through 10 years after the end of the Linxian General Population Nutrition Intervention Trial has shown continued significant reductions in total mortality and gastric cancer mortality among those taking a combination of selenium, beta-carotene and vitamin E, especially among those who were less than the median age (55 years) at the beginning of the trial. Results from nested studies in the NIT cohort have shown: (i) a strong association between low serum selenium levels and increased ESCC and gastric cardia cancer risk; (ii) no relation between serum carotenoids and risk of UGI cancers; (iii) a strong association between low serum alpha-tocopherol levels and increased ESCC risk; (iv) a strong association between low tissue zinc levels and increased ESCC risk; (v) increased risk for both cardia and non-cardia gastric cancer among subjects with positive serology for H pylori; (vi) no association between positive serology for HPV 16, HPV 18, or HPV 73 and ESCC, gastric cardia cancer or non-cardia gastric cancer; (vii) no relation between fumonisin exposure and ESCC risk; (viii) an association between tooth loss and risk of UGI cancers; (ix) an association between self-reported goiter and non-cardia gastric cancer; and (x) associations between several genetic polymorphisms and risk of ESCC and/or gastric cardia cancer. We also found no evidence of HPV DNA or HPV oncogene activity in fresh-frozen tumor samples from 272 consecutive ESCC resection specimens in Linxian. (b) Iran: Results from the Golestan Case-Control Study have shown an significant associations between case status and tobacco use, opium use or both; poor oral hygiene; drinking hot-temperature black tea; and various measures of low socioeconomic status. Comparison of normal esophageal tissue biopsies from cases and controls has shown a striking dose-response relationship between PAH exposure in the esophageal tissue (measured by intensity of immunohistochemical staining with anti-PAH antibodies) and case status, consistent with a causal role for PAH exposure in ESCC carcinogenesis. The participants in the Golestan Cohort Study are being followed annually for vital status and cancer endpoints; through June 2013, there have been 3537 deaths (34% cardiovascular, 22% cancer, 17%stroke) and 1127 incident cancers (19% esophagus, 15% stomach), and fewer than 1% of the cohort has been lost to follow-up. (c) Brazil: Recent results from southern Brazil have show an association between urinary 1-hydroxypyrene glucuronide (a PAH metabolite) and consumption of mate, a local tea which has consistently been associated with ESCC risk. Laboratory analysis of dry mate leaves and mate beverages have shown high levels of PAHs in both. (d) Kenya: We have recently finished a feasibility study for the case-control study of ESCC in western Kenya, and will soon begin the full study of 300 cases and 300 controls. (2) Early Detection of Esophageal Cancer: (a) Primary Screening Studies: We recently completed the first endoscopic screening study of asymptomatic adults in Western Kenya; preliminary results from the 300 participants show that 3% had high-grade and 12% had low-grade esophageal squamous dysplasia. We are currently planning evaluation of several new primary screening tests in China using molecular biomarkers. (b) Endoscopic Evaluation Studies: We recently completed the first field study of high resolution microendoscopy (HRME) for endoscopically distinguishing dysplastic from non-dysplastic Lugol's iodine unstained lesions in the squamous esophagus; analysis of this study, which was performed in China, is ongoing. (c) Endoscopic Therapy Studies: We recently completed the first study of radiofrequency ablation (RFA) for treatment of flat high-grade squamous dysplasia and early invasive ESCC in China; preliminary results from the first 100 patients show complete response (defined as no residual high-grade dysplasia or ESCC in the treated area) at 3 months (after one ablation session) in 72% and complete response at 12 months (after 1-3 ablation sessions) in 90% of patients.